3-sulfonamido-6-chloropyridazines and processes of preparing same



United States Patent 3-=SULFONAMIDO-G-CHLOROPYRIDAZINES AND PROCESSES FPREPARING SAME Margaret M. Rogers and Jackson P. English, Stamford,Conn., assignors to American Cyanamid Company, New York, N. Y., acorporation of Maine No Drawing. Application December 24, 1953, SerialNo. 400,376

7 Claims. (Cl. 260239.7)

This invention relates to p-substitutedbenzenesulfonamido-6-chloropyridazines and to methods of preparing thesame.

In our copending application, Serial No. 233,100, filed June 22, 1951,now U. S. Patent Number 2,671,086, issued March 2, 1954, the preparationof 3,6-dichloropyridazine is described. This application also shows thatthe compound is useful as an intermediate for the preparation of variousother organic compounds including the new compound3-sulfanilamido-fi-chloropyridazine, which in turn, may be converted to3-sulfanilamidopyridazine.

In U. S. Patent No. 2,371,115, issued March 6, 1945, a number ofp-substituted benzene sulfonamidopyridazines are described, which havechemotherapeutic activity and are valuable intermediates for theproduction of azo dyes of extraordinary light fastness. Several methodsof preparing sulfanilamidopyridazines are referred to in that patent.Unfortunately, however, the yields that are obtained are low, only about15 per cent in the last step, and several preceding steps are necessary.Because of this, the commercial development of sulfanilamidopyridazinefor its several purposes has been retarded.

We have discovered that the compound 3,6-dichloropyridazine, which isdisclosed and claimed in our aforesaid prior application, can be made toreact with sulfanilamide and N -acylsult'anilamides to yield(p-substituted benzenesulfonamido)-6-chloropyridazines with very goodyields, and further, these new compounds can be dechlorinated veryreadily to yield (p-substituted bcnzenesulfonaniido) pyridazines. The(p-acylaminobenzenesulfonamido)-6-chloropyridazihes can be readilydeacylated by hydrolysis to yield 3-sulfanilamido-6-chloropyridazines.The new compound 3-sulfanilamido-6-chloropyridazine possessestherapeutic activity and is useful in the synthesis of other organiccompounds, for example, it is an intermediate for the preparation of theknown sulfanilamidopyridazine.

In preparing the compounds of the present invention,3,6-dichloropyridazine is obtained preferably by the process of ourPatent Number 2,671,086, issued March 2, 1954. A method of preparingthis compound will be described in the examples hereinafter. The3,6-dichloropyridazine need not be of a specially high purity in view ofsubsequent purification steps. It is reacted with sulfanilamide orp-acetylaminobenzene sulfonamide by heating at a temperature of 130C.220 C. in the presence of an acid acceptor, such as potassiumcarbonate. The presence of a solvent is not necessary, although highboiling inert solvents, such as the simple hydrocarbons or ch10- rinatedhydrocarbons, may be used if desired.

When using an alkali carbonate as an acid acceptor, the beginning of thereaction will be noted by the evolution of carbon dioxide. The reactionis exothermic and takes place very rapidly once the reaction temperaturehas been reached. Recovery of the benzenesulfonamido-6-chloropyridazineis readily accomplished by methods such as are described in theexamples.

When used as an intermediate for conversion to sulfanilamidopyridazine,the crude product may be used and the chlorine removed by reduction asshown in the examples or by other reducing agents.

The unusual reactivity of 3,6-dichloropyridazine by which one chlorinereadily reacts with the amino group of sulfanilamide to yield3-sulfanilamido-6-chloropyridazine is considered surprising and enablesus to readily prepare 3-sulfanilamido-6-ch1oropyridazine, a usefulcompound in its own right, or allows us to proceed to the preparation ofsulfanilamidopyridazine by removal of the chlorine atom on thepyridazine ring to yield directly the valuable compound3-sulfanilamidopyridazine.

To illustrate the invention in greater particularity, the followingexamples are given. All parts are by weight unless otherwise indicated.

Example I A slurry of one part of maleic hydrazide in 7.1 parts ofphosphorus oxychloride is stirred for fifteen minutes at roomtemperature and then heated to C. Heating is discontinued at this point,as the heat of reaction is sulficient to maintain the reaction at thistemperature. After about twenty minutes the reaction is substantiallycomplete, and excess phosphorus oxychloride is removed by vacuumdistillation. The resulting oily residue is drowned in ice Water, whichresults in the appearance of a copious tan precipitate. This mixture ismade alkaline by the gradual addition of concentrated ammoniumhydroxide, and the mixture is then extracted to exhaustion with ether.The ether solution is dried by treatment for about sixteen hours withcalcium sulfate at 8 C. and is then filtered and concentrated to a smallvolume by evaporation of solvent. The remaining concentrated solution isdistilled in a vacuum and a fraction boiling at 123 C. to 127 C. at 8mm. pressure is collected. This 3,6-dichloropyridazine has a meltingpoint of about 66 C. to 68 C.

Example 11 1.9 parts of 3,6-dichloropyridazine, 3.4 parts ofsulfanilamide, 2.7 parts of potassium carbonate and 1 part of sodiumchloride were ground together. The solid mixture was heated withstirring in a wax bath in a roundbottom flask fitted with refluxcondenser. As the dichloropyridazine and sulfanilamide melted, themixture became a slurry. When the bath temperature had reached C. asudden evolution of CO2 occurred which lasted about five minutes, afterwhich the mixture set in fine granules. When no more CO2 was evolved,the wax bath was removed, and the reaction mixture was heated insulficient water to dissolve and allowed to cool. Unreactedsulfanilamide was collected by filtration. Excess di chloropyridazinewas removed from the filtrate by other extraction. The basic solutionwas chilled and poured into one-half volume of 1:3 acetic acid.Suificient hydrochloric acid was added to bring the mixture to pH 4. Thecrude 3-sulfanilamido-6-chloropyridazine which precipitated was purifiedby solution in 6 parts of 1:100 ammonium hydroxide, charcoal treatmentand precipitation by pouring of the filtrate into dilute acetic acid.This new compound has been found to have physiological activity.

In place of the potassium carbonate used above, it is possible to employother acid acceptor substances such as sodium carbonate, bariumcarbonate, sodium bicarbonate, and the like. Other basic substances suchas sodium hydroxide, potassium hydroxide may be used but, however, withnot such efficient results in view of the tendency of these substancesto react with the dichloropyridazine.

As noted, one of the principal advantages of the invention is that thecompound 3-sulfanilamido-6-chloropyridazine is readily converted to3-sulfanilamidopyridazine by reduction. An example of this will now begiven.

Example III A solution of 1.5 parts of3-sulfanilamido-6-chloropyridazine in 1 part of 40% sodium hydroxide and4 parts of water was shaken under an atmosphere of hydrogen for one hourwith 0.15 part of platinum-charcoal catalyst and 0.15 part of 10%palladium-charcoal catalyst. The solution was filtered free of catalystand poured into 3 volumes of 1:8 acetic acid. Product precipitatedamounting to 53% of theoretical yield. Additional product was obtainedby leaching of the catalyst. These crude materials were purified byheating fifteen minutes with decolorizing carbon in a solution ofvolumes of 1:100 ammonium hydroxide and preciptation of the filtrate bypouring into acetic acid solution. Total recovery of material melting187 C. to 188 C. was 86% of theory. This 3-sulfanilamidopyridazine is aknown compound which has been previously reported as havingsulfanilamide activity.

Example IV 4.3 parts N -acetylsulfanilamide, 2.1 partsdichloropyridazine, 2.8 parts of potassium carbonate, and 1.0 part ofsodium chloride were ground together and heated gently, with stirring.When temperature reached 170 C. an evolution of CO2 occurred and thenthe mixture set to a hard mass. The mixture was dissolved in suflicientwater and allowed to cool. Unreacted N -acetylsulfanilamide wasrecovered by filtration and excess dichloropyridazine was removed fromthe filtrate by ether extraction. The basic solution was chilled andacidified slowly with 1:3 acetic acid to pH 4. The crude 3-N-acetylsulfanilamido-6-chloropyridazine which precipitated was purifiedby solution in 6 parts 1:100 ammonium hydroxide, charcoal treatment andprecipitation by acidifying 'filtrate with 1:3 acetic acid.

Example V 1 part 3-N -acetylsulfanilamido-6-chloropyridazine wasrefluxed with 0.26 part sodium hydroxide and 2.6 parts water forminutes. The solution was chilled and acidified slowly with diluteacetic acid until precipitation was complete. The crude3-sulfanilamido-6-chloropyridazine, which precipitated, was purified bydissolving in 6 parts ammonium hydroxide, treating with charcoal andprecipitation with dilute acetic acid.

4 Example VI A solution of 1.5 parts of 3-N -acetylsulfanilamido-6-chloropyridazine in 1 part of 40% sodium hydroxide and 4 parts of waterwas shaken under a hydrogen atmosphere for one hour with 0.15 partof 10%platinum-charcoal catalyst and 0.15 part of 10% palladium-charcoalcatalyst. The solution was filtered free of catalyst and poured into 5volumes 1:3'acetic acid to precipitate the 3-N-acetylsulfanilamidopyridazine.

Example VII 1 part 3-N -acetylsulfanilamidopyridazine was dissolved in10 parts 10% NaOH and 2 parts water and heated in a boiling water bathfor 30 minutes. The solution was chilled and acidified slowly with 1:3acetic acid. The 3-sulfanilamidopyridazine which formed was filteredoil.

We claim:

1. Compounds of the group consisting of 3-N-acylsulfanilamido-6-chloropyridazines and 3-sulfanilamido-6-chloropyridazine.

2. 3N -acetyl sulfanilamido-6-chloropyridazine.

3. 3-sulfanilamido-6-chloropyridazine.

4. A method of preparing compounds of the group consisting of 3N-acyl-sulfanilamido-6-chlor0pyridazine and3-sulfanilamido-6-chloropyridazine, which comprises the step of heatingtogether compounds of the group consisting of sulfanilamide and N-acyl-sulfanilamide and with a 3,6-dichloropyridazine and an acidacceptor.

5. A method of preparing 3-sulfanilamido-6-chloro pyridazine whichcomprises the step of heating together '3,6-dichloropyridazine,sulfanilamide and an acid acceptor.

6. A method of preparing 3-sulfanilamido-6-chloropyridazine whichcomprises the step of heating together 3,6-dichloropyridazine,sulfanilamide and potassium car- 'bonate.

7. A method of preparing 3-su1fanilamido-6-chloropyridazine whichcomprises the step of heating together 3,6-dichloropyridazine andsulfanilamide to a temperature of at least C. in the presence of an acidacceptor of the group consisting of carbonates and bicarbonates ofmetals.

References Cited in the file of this patent UNITED STATES PATENTS2,371,115 Winnek et al. Mar. 6, 1945 2,533,033 Moore Dec. 5, 19502,671,086 Rogers et al. Mar. 2, 1954

1. COMPOUNDS OF THE GROUP CONSISTING OF3-N4-ACYLSULFANILAMIDO-6-CHLOROPYRIDAZINES AND3-SULFANILAMIDO-6CHLOROPYRIDAZINE.